Chemical process for preparing an optically active aminodiol

ABSTRACT

A process is claimed for preparing [1S(1(α, 2β, 4β)]-4-amino-2-hydroxymethyl -1-cyclopentanol from cis-4-((R)-benzoylamino)-2-cyclopentenecarboxylic acid, methyl ester in five steps. The invention also describes a number of novel intermediates useful in the synthesis of [1S(1α, 2β,4β)]-4-amino-2-hydroxymethyl-1-cyclopentanol.

This application is a 371 of PCT/EP93/02219, filed Aug. 19, 1993.

This invention relates to a new process to an optically active aminodiolwhich may be used to prepare chiral carbocyclic analogues ofnucleosides.

During the past two decades much attention has been given to thesynthesis and biological studies of carbocyclic analogues ofnucleosides. Recently, a number of approaches have appeared in theliterature for the preparation of enantiomerically purecarba-2'-deoxyribonucleotides, for example chemoenzymatically, byasymmetric synthesis and by chromatographic and enzymatic resolution. Akey synthetic precursor of the carbocyclic analogues of2'-deoxyribonucleotides is [1S(1α, 2β,4β)]-4-amino-2-hydroxymethyl-1-cyclopentanol, a compound of formula (I)below first described by L Otvos et al in Tetrahedron Letters, 28 (50),6381-6384, 1987. ##STR1##

This paper described the preparation of the compound of formula (I) froman unsaturated bicyclic lactone,(+)-(1R,5S)-2-oxabicyclo[3.3.0]oct-6-en-3-one. The authors subsequentlyreported in Tetrahedron, 44(19), 6207-6216, 1988 an improved procedurefrom a bicyclic lactone diol.

We now describe herein a novel alternative procedure for the preparationof the compound of formula (I). Thus, according to one aspect of thisinvention, there is provided a multistep process for preparing thecompound of formula (I) as depicted in Scheme 1 hereinafter. ##STR2##wherein R represents a suitable protecting group.

Step a for the preparation of the compound of formula (V) from thecompound of formula (VI) comprises treating (VI) with a suitable basesuch as an organic amine [e.g. 1,5-diazabicyclo[5.4.0]undec-5-ene(DBU)]. The reaction may conveniently be effected in an organic solventsuch as a halogenated hydrocarbon (e.g. dichloromethane) at an elevatedtemperature (e.g. reflux).

Step b for the preparation of the compound of formula (IV) from thecompound of formula (V) comprises treating (V) with a Lewis acid such asaluminium trichloride, zinc chloride, titanium tetrachloride or borontrifluoride etherate in a solvent such as a halogenated hydrocarbon(e.g. dichloromethane) conveniently in admixture with a hydrocarbonsolvent (e.g. toluene) at about room temperature, followed by reductionwith a suitable hydride reducing agent, for example an aluminium hydridereducing agent such as diisobutylaluminium hydride (DIBAL). The DIBALmay conveniently be added as a solution in a hydrocarbon solvent (e.g.toluene) and the reduction carried out at a reduced temperature (e.g. atabout 0° to 10° C.). The reaction may be completed by addition of asuitable inorganic acid such as hydrochloric acid.

Step c for the preparation of compounds of formula (III) from thecompound of formula (IV) comprises treating (IV) with a suitable reagentto introduce the protecting group R. The group R may, for instance,represent an aralkyl group such as benzyl which can be introduced underconventional conditions. Thus, for example, benzylation may be effectedby adding a benzyl halide (e.g. benzyl bromide) to (IV) in a solventsuch as a hydrocarbon (e.g. toluene), preferably in the presence of abase such as an alkali or alkaline earth metal carbonate or bicarbonate(e.g. potassium carbonate).

Step d for the preparation of compounds of formula (II) from compoundsof formula (III) comprises treating (III) with a hindered hydroboratingagent capable of complexing to a tertiary amide such as disiamylboranein a solvent such as an ether (e.g. tetrahydrofuran) at about roomtemperature, followed by peroxide oxidation, for example using hydrogenperoxide. The oxidation step may be carried out in the presence of astrong inorganic base such as sodium hydroxide and at a reducedtemperature (e.g. 0° to 15° C.). The work-up conditions may provide acompound of formula (II) in the form of a salt (e.g. a hydrochloridesalt).

Step e for the preparation of the compound of formula (I) from compoundsof formula (II) comprises a conventional deprotection step. Thus, forexample, when R represents an aralkyl group such as benzyl, thedeprotection step may conveniently be carried out by hydrogenolysis inthe presence of a Noble metal catalyst such as palladium-on-carbon. Thework-up conditions may provide the compound of formula (I) in the formof a salt (e.g. a hydrochloride salt).

The combination of Steps a to e above provides an efficient and highyielding multistep synthesis of the compound of formula (I). Inparticular, the inclusion of a Lewis acid such as aluminium trichloridein process Step b provides an unexpected significant yield increase inproduct (IV), typically a 30 to 40% increase in yield. Furthermore, theuse of a hindered hydroborating agent such as disiamylborane leads to amore regioselective and stereoselective hydroxylation reaction in Stepd.

The preparation of the compound of formula (IV) from the compound offormula (V) (as defined by Step b hereinabove) is a key step in theScheme 1 sequence and thus represents a particular or alternative aspectof the present invention.

The preparation of compounds of formula (II) from compounds of formula(III) (as defined by Step d hereinabove) is another key step in theScheme 1 sequence and thus represents a further particular oralternative aspect of the present invention.

It is to be understood that, in addition to individual Steps b and dabove, any sequential combinations of steps involving Step b and/or Stepd in Scheme 1 represent further particular or alternative aspects of thepresent invention.

The compound of formula (VI) may be prepared by treating the compound offormula (VII) ##STR3## with methanol in the presence of a strong acidsuch as sulphuric acid, conveniently with warming to about 35° to 50° C.

The compound of formula (VII) may be prepared from "(-)Vince Lactam", acompound of formula (VIII) ##STR4##

The acylation reaction may be carried out under conventional conditions,for example by treating (VIII) with a benzoyl halide (e.g. benzoylchloride) in the presence of an organic amine base (e.g. pyridine) atabout room temperature.

The compound of formula (VI) may also be prepared from "racemic VinceLactam" (XII) according to Scheme 2 hereinafter. ##STR5##

Step 1 for the preparation of the compound of formula (XI) from thecompound of formula (XII) comprises acylation following the methoddescribed above for preparing the compound of formula (VII) from thecompound of formula (VIII).

Step 2 for the preparation of the compound of formula (X) from thecompound of formula (XI) comprises treating (XI) with a suitable acidsuch as sulphuric acid or p-toluenesulphonic acid. The reaction mayconveniently be carried out in an organic solvent such as acetonitrileor an ether (e.g. tetrahydrofuran) at an elevated temperature (e.g.reflux).

Step 3 for the preparation of the compound of formula (IX) from thecompound of formula (X) comprises treating (X) with a suitable chiralresolving agent. Chiral resolving agents capable of effecting thedesired conversion will be familiar to persons of ordinary skill in theart. One such suitable agent is R-(+)-α-methylbenzylamine which may bereacted with the compound of formula (X) in a solvent such asacetonitrile, optionally containing water, to provide the salt offormula (XIII) ##STR6## which may then be hydrolysed to the desiredcompound (IX) by addition of a suitable base such as sodium hydroxide.

Step 4 for the preparation of the compound of formula (VI) from thecompound of formula (IX) comprises treating (IX) with methanolichydrogen chloride at about room temperature.

The compounds of formulae (VIII) and (XII) are known compounds describedin J. Chem. Soc. Perkin Trans. 1, 1992, (5), 589-592 and TetrahedronLetters, 1976, (35), 3005-3008 respectively.

The compounds of formulae (II), (III), (IV), (V), (VI), (VII), (IX),(X), (XI) and (XIII) are novel intermediates and represent furtheraspects of the present invention. The compound of formula (VI) is a keynovel intermediate and represents a particular aspect of the presentinvention.

The following non-limiting examples illustrate the invention.

Preparation 1 (step 1)

(±)-2-Benzoyl-2-azabicyclo [2.2.1]hept-5-ene-3-one (Intermediate XI)

Intermediate (XII) ("Racemic Vince Lactam") (32.3 g) was dissolved inpyridine (163 mL). The solution was cooled in ice while benzoyl chloride(50 mL) was added over approximately 10 minutes. The resulting dark redmixture was stirred at room temperature for 2 hours and then cooled to15° C. Distilled water (490 mL) was added over 20 minutes and thedeveloping slurry was stirred for 1 hour at room temperature then for 30minutes at 10°-15° C. The solid was collected by vacuum filtration,washed thoroughly with water and dried at 50° C. under reduced pressureto afford the title compound (54 g).

δ (DMSO.d₆): 7.7-7.35 (5H,m); 7.07 (1H,m); 6.69 (1H,m); 5.08 (1H, m);3.42 (1H,m); 2.49 (1H,m); 2.19 (1H,m).

Mpt=110° C.

Preparation 2 (step 2)

cis-4-(Benzoylamino)-2-cyclopentene carboxylic acid (Intermediate X)

Intermediate (XI) (53 g) was dissolved in acetonitrile (410 mL) anddecolourizing charcoal (12 g) was added. The mixture was stirred for 30minutes at room temperature then filtered under vacuum through a bed ofcelite directly into a 1 liter round bottomed flask. Acetonitrile (140mL) was used to wash the pad of celite. p-Toluenesulphonic acidmonohydrate (4.75 g) and water (9.0 mL) were added and the stirredmixture was heated under gentle reflux for 1.5 hours. The stirredmixture was then cooled to room temperature over approximately 1 hour.Stirring was continued at this temperature for a further 1 hour beforecooling to 10° C. for a further 1.5 hours. The deposited solid wascollected by vacuum filtration, washed with acetonitrile (2×70 mL) anddried at 40° C. under vacuum to give the title compound (47.6 g).

δ (DMSO.d₆): 8.44 (1H, d, 6); 7.88 (2H, d, 8); 7.60-7.35 (3H,m);6.00-5.80 (2H,m); 5.02 (1H,m); 3.52 (1H,m); 2.65-2.45 (1H,m); 2.05-1.80(1 H,m).

Mpt=169° C.

Preparation 3 (step 3)

(R)-4-(Benzoylamino)-2-cyclopentene carboxylic acid (Intermediate IX)

Intermediate (X) (76 g) in acetonitrile (2.3 liters) and distilled water(105 mL) were stirred and warmed to 40°-45° C. A solution of(R)-(+)-α-methylbenzylamine (39.9 g) in acetonitrile (330 mL) was addedat 45° C. to give a clear almost colourless solution. After 10 minutescrystallisation had begun. The continuously stirred mixture was cooledslowly over 90 minutes to room temperature, then chilled in ice water at0°-5° C. for 2 hours. The deposited solid was collected by vacuumfiltration, washed with chilled acetonitrile (3×140 mL) and dried at40°-45° C. under reduced pressure overnight to give intermediate (XIII)(53.4 g). A suspension of intermediate (XIII) (52.9 g) in distilledwater (530 mL) and methyl isobutyl ketone (530 mL) was stirred and thepH adjusted from approximately 6.7 to 9.5 by the slow addition of 2Maqueous sodium hydroxide solution. Stirring was continued for a further30 minutes before the layers were allowed to separate. The aqueous layerwas run off and re-extracted with methyl isobutyl ketone (150 mL). Theseparated aqueous layer was stirred and acidified to pH<2 by slowaddition of 3M aqueous hydrochloric acid. The resulting slurry wasstirred for 2 hours cooling to 10° C. and filtered. The solid was washedwith distilled water and dried at 40°-50° C. under reduced pressure togive the title compound (33.2 g).

δ (DMSO.d₆): 8.49 (1H, d, 6); 8.00-7.80 (2H,m); 7.60-7.40 (3H,m);6.00-5.80 (2H,m); 5.04 (1H,m); 3.54 (1 H,m); 2.65-2.45 (1 H,m);2.05-1.85 (1H,m).

Mpt=146° C.

[α]_(D) ²⁰ +24° (c=0.5%, MeOH).

Preparation 4 (step 4)

cis-4-((R)-Benzoylamino)-2-cyclopentenecarboxylic acid, methyl ester(Intermediate VI)

Intermediate (IX) (37.8 g) in methanolic hydrogen chloride (260 mL, 4.5%w/w) was stirred at room temperature for 1.25 hours. The solution wasconcentrated under reduced pressure to a residual volume of 95 mL. Tothe resulting stirred solution was added distilled water (380 mL). Theresulting suspension was stirred and cooled to between 5° and 10° C. for2 hours. The solid was collected by vacuum filtration, washed with water(3×100 mL) and dried at 50° C. under reduced pressure to yield the titlecompound (37 g).

δ (DMSO.d₆): 8.56 (1H, d, 6); 8.05-7.85 (2H,m); 7.70-7.40 (3H,m);6.10-5.85 (2H,m); 5.09 (1H,m); 3.71 (3H,s); 3.67 (1H,m); 2.80-2.50(1H,m); 2.10-1.90 (1H,m).

Mpt=84° C.

[α]_(D) ²⁰ =+14 (c=0.5%, MeOH).

Preparation 5 (step a)

(S)-4-(Benzoylamino)-1-cyclopentene carboxylic acid methyl ester(Intermediate V)

Intermediate (VI) (20 g) was dissolved in dichloromethane (100 mL) and1,5-diazabicyclo [5.4.0] undec-5-ene (17.4 mL) was added. The reactionwas stirred at reflux for 6 hours before cooling to room temperature.Stirring was continued at room temperature overnight. The batch wascooled to 0° C. and ice (30 g ), water (20 mL) and concentratedsulphuric acid (6.0 mL) were added. The organic phase was separated andwashed with water (50 mL). Concentration of the separated organic phaseunder reduced pressure yielded a soft solid which was triturated withdiisopropyl ether (50 mL). The product was collected by filtration,washed with diisopropyl ether and dried under vacuum to give the titlecompound (18.76 g).

δ (DMSO.d₆) 8.59 (1H,d,₆); 7.89 (2H,m); 7.60-7.35 (3H,m); 6.78 (1H,m);4.62 (1H,m); 3.73 (3H,s); 3.05-2.80 (2H,m); 2.70-2.40 (2H,m).

Preparation 6 (step b)

(S)-N-[3-(Hydroxymethyl)-3-cyclopentenyl]-benzamide (Intermediate IV)

Intermediate (V) (40 g) was suspended in a mixture of dichloromethane(200 mL) and toluene (100 mL) and the suspension was cooled toapproximately 3° C. Aluminium trichloride (21.75 g) was added and thereaction mixture was stirred for 20 minutes to give a cloudy solution.The resultant mixture was then cooled to 0° C. and a solution ofdiisobutylaluminium hydride in toluene (100 mL, 375 mmol ofdiisobutylaluminium hydride) was added at a rate such that the reactionmixture remained in the temperature range of 0°-10° C. Upon completionof the addition of the diisobutylaluminium hydride the reaction mixturewas stirred for 10 minutes at 0°-5° C. After this time the mixture wasadded over 16 minutes to a solution of concentrated hydrochloric acid(100 mL) in water (200 mL) at room temperature. Toluene (100 mL) wasadded and stirring continued for a further 30 minutes. The reactionmixture was then cooled to 5° C. and stirred at this temperature for 1hour. The product was harvested by filtration and washed with toluene(2×80 mL), 2M hydrochloric acid (40 mL) and water (40 mL). Drying undervacuum yielded the title compound (32.36 g).

δ (DMSO.d₆): 8.49 (1H,d,6); 7.87 (2H,m); 7.60-7.40 (3H,m); 5.51 (1H,m);4.70 (1H,m), 4.60 (1H,m); 4.60 (1H,m); 3.99 (2H,s,broad); 2.80-2.55(2H,m); 2.45-2.20 (2H,m).

n (max, nujol): 3389 cm⁻¹, 3315 cm⁻¹, 1629 cm⁻¹.

Preparation 7 (step c)

(S)-N-(Phenylmethyl)-N-[3[(phenylmethoxy)methyl]-3-cyclopentenyl]-benzamide(Intermediate III)

Intermediate (IV) (500 g) was added to t-butyl methyl ether (5 L) andthe resultant suspension stirred at room temperature while potassiumcarbonate (1906 g), tetra-n-butylammonium hydrogen sulphate (117 g) andsodium hydroxide (644 g) were added sequentially. Stirring was continuedwhile the internal temperature was raised to reflux via a hot waterbath. Reflux was continued for a further 25 minutes and then benzylbromide (600 ml) was added dropwise to the refluxing suspension. Refluxwas continued for a further 160 min. with further benzyl bromide (25 ml)added after 2 h. Heating was discontinued and methanol (25 ml) addedover 30 seconds. The mixture was then cooled to 30.8° C. and distilledwater (5×1 L) added over 4 minutes. The mixture was further cooled witha cold water bath, transferred to a glass separating flask via vacuumand the lower aqueous phase removed. The aqueous phase was extractedwith t-butyl methyl ether (1 L) and the organic phases combined andwashed with distilled water (3×2.5 L). The organic phase wasconcentrated to 1.25 L and stirred for 20 minutes. Petroleum ether(60°-80°, 2 L) was then added dropwise and stirring continued for afurther 20 minutes. After refrigeration overnight, the resulting solidwas filtered off and washed with chilled petroleum ether (60°-80°, 2×1L) under vacuum. The solid was then dried to give the title compound(737.6 g).

δ (DMSO.D₆): 7.1-7.6 (15H, m), 5.52 (1H, broad s), 4.6 (3H, m), 4.38(2H, s), 3.90 (2H, s), 2.40 (4H, broad m).

Mpt=74°-75° C.

Preparation 8 (step d)

[IS(1α,2β,4β)]-4-[(Phenylmethyl)amino]-2-[(phenylmethoxy)methyl]-1-cyclopentanol(Intermediate II)

2-methyl-2-butene (202 ml) was added to tetrahydrofuran (198 ml) and theresulting solution stirred under nitrogen and cooled to 0° C. Boranedimethylsulphide complex (90.6 ml) was then added at a rate such thatthe temperature of the mixture did not exceed 24° C. This solution wasthen stirred and treated with a solution of Intermediate (III)(120 g) intetrahydrofuran (240 ml) over 40 minutes. Stirring was continued for 24h at ca 23°-26° C. and then the reaction quenched by cooling thesolution to 0° C. and adding dropwise a mixture of water (10.9 ml) andtetrahydrofuran (120 ml). The solution was re-cooled to 0° C. and then3M sodium hydroxide (302 ml) added over 12 minutes. Thesolution/emulsion obtained was cooled to -20° to -25° C. and hydrogenperoxide (30%, 308 ml) added dropwise over ca 2 hours such that aninternal temperature of <30° C. was maintained. 98 minutes from the endof the hydrogen peroxide addition a solution of sodium sulphite (60 g)in water (240 ml) was added over 70 minutes. Following the finaladdition of hydrogen peroxide the mixture was left under nitrogenovernight. The mixture was then stirred and methyl isobutyl ketone (600ml) was added. The phases were separated and the aqueous phase wasextracted with methyl isobutyl ketone (240 ml). The combined organicphases were washed with water (4×240 ml) and the organic phase reducedto ca 600 ml volume. The resulting yellow solution was stirred andcooled to 4° C. and then concentrated hydrochloric acid (25 ml) wasadded. The cooling bath was removed and after 30 minutes t-butyl methylether (600 ml) was added dropwise. The pH was lowered to 1-2 during theaddition of t-butyl methyl ether by further addition of concentratedhydrochloric acid (0.5 ml). The resulting suspension was stirred for ca1 h with ice/water cooling and then filtered. The residual white solidwas washed with t-butyl methyl ether (3×240 ml) and then dried to givethe title compound (89.7 g).

δ (DMSO.d₆): 9.6 (2H, broad), 7.7-7.2 (10H, m), 4.90 (1H, broad), 4.48(2H, AB), 4.10 (2H, m), 3.98 (1H, m), 3.5 and 3.35 (3H, m), 2.25,1.8-2.1, 1.52 (5H, m).

Mpt=136°-138° C.

Preparation 9 (step e)

[1S(1α,2β,4β)]-4-Amino-2-hydroxymethyl-1-cyctopentanol

Intermediate (II) (100 g) was dissolved in isopropanol (250 mL) andwater (80 mL). Charcoal (50 g) was added and the mixture stirred for 30minutes. After this time celite (25 g) was added and the mixturefiltered through a bed of celite. The filter bed was washed with amixture of isopropanol (125 mL) and water (40 mL) twice. The filtrateand washes were combined. 5% Palladium on charcoal (100 g) was chargedinto a dry flask. The flask was purged with nitrogen and the combinedfiltrate and washes from above were added. The resulting mixture wasstirred and heated to approximately 50° C. under an atmosphere ofhydrogen for 3 hours. After this time the reaction mixture was allowedto cool and then filtered through a pad of celite. The filter pad wasthen washed with mixtures of isopropanol and water. The combinedfiltrate and washings were evaporated to approximately 400 mL. n-Butanol(200 mL) was added and the mixture re-evaporated under reduced pressureto 50 mL. Methanol (40 mL) containing concentrated hydrochloric acid (2mL) was added followed by n-butanol (200 mL). The solvent was removedunder reduced pressure to yield a gum. This was taken up in methanol andthe volume reduced under pressure to the point at which crystallisationhad just begun. The mixture was seeded with an authentic sample of thetitle compound and acetone (200 mL) was added slowly. Filtrationfollowed by washing with n-butanol/acetone (1:1, 100 mL) and acetone(100 mL) yielded after drying, under reduced pressure, the titlecompound (39.3 g).

δ (DMSO:d₆): 8.20 (3H,s,broad); 4.90-4.50 (2H,m,broad); 3.94 (1H,m);3.53 (1H,m); 3.50-3.25 (2H,m); 2.13 (1H,m); 1.95-1.70 (3H,m); 1.34(1H,m).

Analysis Found: C=43.5, H=8.8, N=8.3,

Requires: C=43.0, H=8.4, N=8.4.

Preparation 10

(-)2-Benzoyl-2-azabicyclo[2.2.1]hept-5-ene-3-one (Intermediate VII)

A solution of Intermediate (VIII) ("(-)Vince Lactam") (1.4 kg) inpyridine (50 L) under nitrogen at ca 10° C. was treated with benzoylchloride (15 L), keeping the temperature below 25° C. The mixture wasstirred at 20° to 30° C. for 2.5 h, cooled to ca 10° C. and treated withwater (30 L) over ca 30 minutes. Further water (120 L) was added and themixture stirred at 5° C. overnight. The resulting solid was filtered,washed with water (4×20 L) and dried to give the title compound (16.9Kg).

δ (DMSO.d₆): 7.7-7.4 (5H, m), 7.05 (1H, m), 6.70 (1H, m), 5.07 (1H, m),3.42 (1H, broad s), 2.50 (1H, d), 2.18 (1H, d).

Mpt=153° C.

Preparation 11

cis-4-((R)-Benzoylamino)-2-cyctopentenecarboxylic acid, methyl ester(Intermediate VI)

Concentrated sulphuric acid (2.64 L) was added over 10 minutes to astirred suspension of Intermediate (VII) (13.27 Kg) in methanol (60 L).A further 8 L methanol was added to the suspension which was slowlywarmed to 47° C. The resulting solution was cooled to 25° C. andtriethylamine (8.6 L) added over ca 10 minutes followed by water (90 L).Further triethylamine (3×200 ml) was added to give a final pH of ca7-7.5. The methanol was distilled off in vacuo during which time furtherwater (40 L) was added portionwise. The resulting slurry was cooled to0° C. and stirred at this temperature overnight. The resulting solid wasfiltered, washed with water (3×25 L) and dried to give the titlecompound (14.42 Kg).

δ (DMSO.d₆): 8.55 (1H, d), 7.84 (2H, m), 7.6-7.4 (3H, m), 5.90 (2H, m),5.02 (1H, m), 3.60 (1H, m) 2.58 (1H, dt), 1.92 (1H, dt).

Mpt=86° C.

We claim:
 1. A process for the preparation of a compound of formula (I)##STR7## or a salt thereof from a compound of formula (VI) ##STR8##which comprises: Step a: treating a compound of formula (VI) with asuitable base to provide a compound of formula (V) ##STR9## Step b:treating the so-formed compound of formula (V) with a Lewis acid,followed by reduction with a suitable hydride reducing agent to providea compound of formula (IV) ##STR10## Step c: protecting the so-formedcompound of formula (IV) to provide a compound of formula (III)##STR11## where R is a protecting group Step d: treating the so-formedcompound of formula (III) with a hindered hydroborating agent capable ofcomplexing a tertiary amide, followed by peroxide oxidation to provide acompound of formula (II) ##STR12## where R is a protecting group andStep e: deprotecting the so-formed compound of formula (II) to providethe desired compound of formula (I).
 2. A process for preparing acompound of formula (IV) ##STR13## comprising treating a compound offormula (V) ##STR14## with a Lewis acid, followed by reduction with asuitable hydride reducing agent.
 3. A process as claimed in claim 2 inwhich the Lewis acid is aluminium trichloride.
 4. A process as claimedin claim 2, which comprises treating a compound of formula (V) withaluminum trichloride in a solvent, followed by reduction with analuminum hydride reducing agent.
 5. A process for preparing a compoundof formula (II) ##STR15## where R is a protecting group comprisingtreating a compound of formula (III) ##STR16## where R is a protectinggroup with a hindered hydroborating agent capable of complexing to atertiary amide, followed by peroxide oxidation.
 6. A process as claimedin claim 5 in which the hydroborating agent is disiamylborane.
 7. Aprocess as claimed in claim 5 which comprises treating a compound offormula (III) with disiamylborane in a solvent followed by peroxideoxidation.
 8. A process for preparing a compound of formula (IX)##STR17## which comprises treating a compound of formula (X) ##STR18##with R-(+)-α-methylbenzylamine to provide a compound of formula (XIII)##STR19## and then hydrolysing the so-formed compound of formula (XIII)under basic condition to provide the desired compound of formula (IX).9. cis-4-((R)-Benzoylamino)-2-cyclopentenecarboxylic acid, methyl ester.10. The compounds of the following formulae: ##STR20##